The suppression of ATR/Chk1 pathway by Elimusertib ATR inhibitor in triple negative breast cancer cells.

OBJECTIVES

Genomic instability in cancer cells is based on the aberrant activation of deoxyribonucleic acid (DNA) damage response and repair mechanisms. Targeting Ataxia telangiectasia and Rad3-related (ATR) inhibition in cancer treatment have attracted attention in recent years. In the current study, we aimed for the first time to determine the anti-cancer effects of Elimusertib, an ATR inhibitor, on triple negative breast cancer (TNBC).

METHODS

The cytotoxic and apoptotic effects of Elimusertib were analyzed by Water-Soluble Tetrazolium 1 (WST-1), Annexin V, cell cycle and acridine orange/propidium iodide staining. Furthermore, Elimusertib induced mitochondrial damage and the intracellular reactive oxygen species were evaluated. Additionally, the inhibition of ATR-Checkpoint kinase 1 (Chk1) DNA damage response and the induction of apoptotic death was analyzed by western blot analysis.

RESULTS

Our preliminary findings revealed that Elimusertib significantly decreased the viability of MDA-MB-231 TNBC cells with toxicity in MCF-10A cells (P<0.05). Elimusertib caused apoptotic death through gap phase (G0)/growth 1 phase (G1) accumulation, caspase-3 activity and mitochondrial damage. Additionally, Elimusertib significantly suppressed the ATR-based DNA damage response and mediated cell cycle checkpoint.

CONCLUSIONS

Our findings suggest that Elimusertib suppresses the ATR-based Chk1 pathway in TNBC cells. Therefore, ATR inhibition by Elimusertib could be a potential therapeutic strategy especially in tumor protein p53 (p53) mutant TNBC patients.